Oct4/Sox2/Klf4/c-Myc (OSKM)-induced reprogramming is a stepwise process that allows differentiated cells to reach pluripotency. It is marked by the emergence of cellular intermediate states characterized by the activation of a pluripotent network, a progressive gain of cellular plasticity & a loss of cellular identity. In vivo reprogramming represents a promising strategy for tissue regeneration. Although several tissues have been described as amenable to reprogramming in vivo, lung tissue was considered refractory due to its intricate architecture as well as its cell type diversity. Recent studies suggest that lung tissue has a high regenerative capacity due to progenitor cells, where upon tissue damage, they proliferate & differentiate into a needed cell type, allowing regeneration. Despite the lung cell plasticity, the fact that it’s refractory to in vivo reprogramming highlights the existence of cellular barriers that are not well understood in vivo. Therefore, we aimed to decipher the molecular & epigenetic mechanisms involved in controlling lung tissue from reprogramming in vivo. To do so, we used a newly developed reprogrammable mouse model allowing the specific expression of OSKM transcription factors in the lung tissue. In this model, the reprogramming cells are followed by an mKate2 fluorescent reporter. The study showed a progressive loss of mKATE2 labeled cells undergoing reprogramming from day 4 to day 10 of OSKM induction. This result suggests the presence of a barrier that prevents cells from completing reprogramming & reaching full pluripotency. Single-cell RNA-Seq analyses identified an enrichment of an immune response signature at 7 days of in vivo reprogramming. In accordance, immunofluorescence analyses next revealed an infiltration of innate immune cells (Macrophages) following lung in vivo reprogramming. Furthermore, a proteome profile cytokine array showed an increased secretion of chemokines responsible for innate immune cells recruitment. These data indicate that lung reprogramming may alter cell identity, potentially leading to an immune response activation, which in turn could represent an important barrier preventing full reach of pluripotency. We aim to conduct a functional validation in vivo & ex vivo to support our claims. This study provides insights into understanding the complex interplay between OSKM-induced in vivo reprogramming & the immune microenvironment, opening new perspectives in the context of lung regeneration.